Why Do Transcription Factors Bind To Intronic Regions Downstream Of The Transcription Start Site?

Question

[14134125465346445]

What is the explanation for transcription factors to bind to intronic regions downstream of the transcription start site?

Given that the most common model for transcriptional activation is that binding just upstream of the transcription start site (TSS) help place polymerase II at the beginning of the gene, what would be the reason to have binding sites for the same transcription factor peppered around introns in the same target genes?

[Russh]

My favourite gene had a bit of that: http://www.ncbi.nlm.nih.gov/pubmed/14623874 Maybe it makes sense for some TFs to be displaced by RNAPol

Answer 1

[Steve Lianoglou]

One thing to note is that not all binding is functional, so just because a TF is binding somewhere, it doesn't necessarily mean it's doing anything.

A "simple" explanation that fits with your intuition could be that these could just be alternative transcription start sites, no?

BUT, the who/what/where/when/how of transcriptional regulation is still a mysterious place to explore. There are many regulatory regions of DNA that don't follow "the most common model of transcriptional activation" that you outline in your question. Why wouldn't introns be a reasonable place to bind? The notion of binding "before" and "after" a transcriptional unit only makes sense when you read the DNA sequence from left to right, but the landscape of DNA seems to be more like the dream landscapes from Inception with folds, twists, turns, loops, etc. than the more traditional highway 66.

The hunt for regulatory DNA has just begun. Cf. the buzz around the high-throughput chromatin conformation capture experiments (hi-c, chia-pet, 5C).

Some random references.

• Topological domains in mammalian genomes identified by analysis of chromatin interactions

• Shadow Enhancers as a Source of Evolutionary Novelty

[Obi Griffith]

Great answer Steve. Another simple possibility is that when a TF binds in the intron of one gene it is actually part of the transcriptional regulation of another nearby gene (e.g., acting as a distal enhancer).

[Steve Lianoglou]

Thanks, Obi. Yeah, you make a good point. In fact, there is even such an example of a "shadow enhancer" that fits that MO as well, which should be in that Levine paper I linked ;-) I actually haven't read the paper, but only saw Levine present that work and he pointed out such examples (so I'm assuming it's in the paper as well). Really cool stuff.

Answer 2

[Frenkiboy]

The following paper is an interesting reading on the topic:

Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation

It seems the more we know about the regulatory landscape, the messier it gets :)